Báo cáo y học: "Biology of recently discovered cytokines: Discerning the pro- and anti-inflammatory properties of interleukin-27" pptx

225
BCG = bacille Calmette-Guérin; DC = dendritic cell; EBV = Epstein–Barr virus; EBI3 = Epstein–Barr virus-induced gene 3; HMDC = human
monocyte derived dendritic cell; IFN = interferon; IL = interleukin; IL-27R = Interleukin-27 receptor Jak = Janus kinase; LPS = lipopolysaccharide;
NK = natural killer; STAT = signal transducer and activator of transcription; Th = T-helper; TLR = Toll-like receptor; TNF = tumor necrosis factor.
Available online />Introduction
IL-27 is a heterodimeric member of the IL-6/IL-12 family of
type I cytokines [1,2]. Like IL-12 and IL-23 [1], IL-27 is the
pairing of a helical protein (IL-27p28) with a soluble
cytokine receptor-like component (Epstein–Barr virus-
induced gene 3 [EBI3]; Fig. 1) [1,3]. Similar to IL-12p40
and soluble forms of IL-6 receptor components [4], EBI3
contains two cytokine binding domains but lacks
membrane anchoring motifs and a cytoplasmic tail (Fig. 1)
[5]. Originally identified as an IL-12p40 homolog that is
secreted by Epstein–Barr virus (EBV) transformed B cells
[5], EBI3 is produced by a range of immune cell lineages
including B cells, monocytes, dendritic cells (DCs) and
epithelial cells [3,5–7].
While typically low or absent in resting cells, EBI3
expression is constitutive in several human lymphomas [8]
and can be elicited by pathogen and host derived
inflammatory stimuli [3,5,6]. For instance, in B cells, EBI3
production is directly induced by EBV latent membrane
protein 1 [9]. Likewise, monocytes and DCs secrete EBI3
in response to lipopolysaccharide (LPS), CD40 ligation or
exposure to inflammatory cytokines [3,6,10,11]. Since
production of EBI3 is limited to activated immune cells,
expression levels are highest in the spleen [3,5,6], lymph
nodes [3,5,6], placenta [12,13] and sites of chronic
inflammation [7,14–16]. Thus the induction by inflammatory
stimuli and its prevalence in lymphoid tissues suggest that

EBI3 plays a role in the regulation of immune responses.
Since EBI3 shows no direct activity on its own [5], it is
likely that, like IL-12p40, it must associate with other
proteins to form bioactive cytokines. One dimeric partner
for EBI3 is IL-27p28 (Fig. 1), a helical cytokine that was
identified through its homology to IL-12p35 and IL-6 [3].
While it is possible that IL-27p28 can associate with other
proteins, expression of this gene is only detected
concurrently with that of EBI3 [3,6,10,17–20]. As with
IL-12p35, IL-27p28 gene transcription is tightly regulated
and the protein is poorly secreted unless it is co-
expressed with a soluble receptor-like component
(IL-12p40 and EBI3 respectively) [3]. In macrophages,
DCs and epithelial cells, the same inflammatory stimuli
that promote IL-27p28 transcription also induce
Review
Biology of recently discovered cytokines: Discerning the pro- and
anti-inflammatory properties of interleukin-27
Alejandro V Villarino and Christopher A Hunter
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Corresponding author: Christopher A Hunter,
Received: 25 Jun 2004 Accepted: 21 Jul 2004 Published: 16 August 2004
Arthritis Res Ther 2004, 6:225-233 (DOI 10.1186/ar1227)
© 2004 BioMed Central Ltd
Abstract
IL-27 is a recently identified heterodimeric cytokine produced in response to microbial and host
derived inflammatory cues. Initial studies indicated that IL-27 promotes the generation of Th1
responses required for resistance to intracellular infection and unveiled the molecular mechanisms
mediating this effect. However, subsequent work uncovered a role for IL-27 in the suppression of Th1
and Th2 responses. Thus, by discussing its pleotropic functions in the context of infection-induced

immunity and by drawing parallels to fellow IL-6/IL-12 family cytokines, this review will attempt to
reconcile the pro- and anti-inflammatory effects of IL-27.
Keywords IL-27, WSX-1, Th1, Th2, infection
226
Arthritis Research & Therapy Vol 6 No 5 Villarino and Hunter
expression of EBI3, thus prompting secretion of
heterodimeric IL-27 [3,6,7,17–20]. Pathogenic
Streptoccocus pyogenes can elicit IL-27 production from
human monocyte derived DCs (HMDCs) but commensal
Gram-positive bacteria do not [19,20]. Conversely,
exposure of HMDCs to non-pathogenic Gram-negative
bacteria promotes strong IL-27 expression [19] and,
correspondingly, LPS induces production of IL-27 by
HMDCs, murine bone marrow derived macrophages and
murine DCs [3,6,17]. Many of the stimulatory effects of
LPS are mediated through Toll-like receptor 4 (TLR4) but
other host pattern recognition receptors can also trigger
IL-27 expression. Ligation of TLR9 with double stranded
DNA leads to strong induction of IL-27 in murine bone
marrow derived DCs and engagement of TLR2 with its
synthetic ligand (Pam3Cys) promotes a similar but weaker
IL-27 response in these cells [18]. Together, these studies
demonstrate that bacterial products can directly induce
IL-27 production but do not account for the elevated
expression of this cytokine during infection with eukaryotic
pathogens, such as Toxoplasma gondii and Trichuris
muris [21–23]. However, since a variety of host derived
factors, including CD40 ligation, IFN-β, and IFN-γ, can
promote IL-27 expression [3,6,10,17], it is unclear
whether the appearance of this cytokine can be directly

attributed to parasite elements or the host response to
infection. Nonetheless, these findings indicate that IL-27 is
generated in response to various inflammatory stimuli and
imply a role for this cytokine in the regulation of infection-
induced immunity.
Because they promote inflammatory processes, the
production of heterodimeric IL-6/IL-12 family cytokines is
tightly regulated. However, for both IL-12 and IL-27,
transcription of the soluble receptor component
(IL-12p40/EBI3) is always greater than that of the helical
subunit (IL-12p35/IL-27p28) [3,6,24,25]. In the case of
IL-12p40, it can also dimerize with the IL-6/IL-12 family
protein IL-23p19 to form IL-23, a cytokine that promotes
the development of infection induced and autoimmune
inflammatory responses [24–28]. Therefore, since it can
be expressed in the absence of IL-27p28, it is tempting to
speculate that, like IL-12p40, EBI3 can participate in
multiple cytokines. While an association between EBI3
and IL-12p35 was described several years prior to the
identification of IL-27, no distinct function has been
ascribed to this hematopoietin [29]. It is possible that, like
the sequestering of IL-6 by soluble receptor components
(e.g. soluble IL-6 receptor and soluble GP130) [4], this
EBI3 heterodimer acts as a molecular sink that limits the
availability of IL-12p35 for inclusion in bioactive IL-12
(Fig. 1) [29]. However, since IL-27 can have dramatic and
direct effects on a variety of cell types (Detailed
discussion below), it is likely that IL-27p28 is the more
biologically relevant partner for EBI3.
The interleukin-27 receptor complex

All IL-6/IL-12 family cytokines propagate intracellular
signaling through transmembrane receptor complexes that
include either IL-12Rβ1 or GP130 [1]. Restricted to
mature lymphoid cells, IL-12Rβ1 is a component in the
heterodimeric receptors for IL-12 and IL-23 [24,25].
Accordingly, IL-12Rβ1 defects result in enhanced
susceptibility to intracellular infection and compromised
adaptive immunity [30,31]. In contrast, GP130 is
expressed throughout development by a range of immune
and non-immune cells [32]. Because GP130 is a
component in heterodimeric receptors for several
cytokines, including IL-6, IL-11, LIF (leukemia inhibitory
factor), G-CSF (granulogyte colony-stimulating factor) and
Oncostatin M [4,32], germline deletion of this gene leads
Figure 1
IL-27 and the IL-27 receptor complex. Heterodimeric IL-27 is the
association between a helical protein, IL-27p28, and a soluble cytokine
receptor-like component, EBI3. Through engagement of its cognate
receptor, (IL-27R: GP130/WSX-1), IL-27 can activate a
heterogeneous Jak/STAT signaling cascade. In order to emphasize
structural similarities, IL-27 is depicted with fellow IL-6/IL-12 family
cytokines and the conserved WSXWS motif is represented by a dark
band within cytokine binding domains. To indicate functional parallels,
the relative ability to activate STAT transcription factors is reflected by
differences in font size. However, in this figure, the physical size of
cytokine/receptor pairings or their components does not have
physiological relevance. IL, interleukin; Jak, Janus kinase; STAT, signal
transducer and activator of transcription.
227
to gross developmental defects [33]. Therefore, due to the

broad distribution of this shared receptor component, the
distinct functions and tissue tropisms of GP130
associated cytokines are determined by the availability of
ligand specific co-receptors [32].
Recent studies have reported that GP130 can associate
with WSX-1 (TCCR), a type I cytokine receptor with four
positionally conserved cysteine residues and a C-terminal
WSXWS protein sequence motif (Fig. 1) [34]. WSX-1
binds to IL-27 with high affinity [3] but requires
cooperation with GP130 to form an IL-27 receptor
(IL-27R) complex that is capable of propagating
intracellular signaling [34]. Coexpression of GP130 and
WSX-1 (IL-27R) can be found in a variety of immune cell
types including activated endothelial cells, activated
epithelial cells, activated DCs, monocytes, mast cells and
B cells. However, expression of IL-27R is greatest in the
lymphoid lineage, particularly in NK and T cells (Fig. 2)
[34–37]. Thus, like its ligand IL-27, IL-27R is restricted
mainly to sites of immune involvement like the spleen,
thymus, lungs, intestine, liver, peripheral blood and lymph
nodes [35,36].
As with other type I cytokine receptors [1,38], ligation of
IL-27R by its cognate ligand results in the activation of a
heterogeneous Janus kinase (Jak)/signal transducer and
activator of transcription (STAT) signaling cascade
(Fig. 1). The binding of IL-27 to IL-27R induces
phosphorylation of: Jak1, STAT1, STAT3, STAT4 and
STAT5 in T cells [6,21,34,39,40]; Jak1, STAT1, STAT3
and STAT5 in NK cells [6,40]; STAT1 and STAT3 in
monocytes [34] and STAT3 in mast cells [34]. Together

with the limited distribution of WSX-1, the ability to
activate Jak/STAT signaling pathways implies that the
principal function of the IL-27R, like that of fellow GP130
user IL-6R (Fig. 1), is in the regulation of immune
processes.
Interleukin-27 can promote type I
inflammatory responses
IL-6/IL-12 family cytokines play key roles in the generation
and regulation of inflammatory responses [24,25,32]. For
instance, IL-12 promotes resistance to intracellular
infection by inducing the production of IFN-γ, the signature
cytokine of type I (Th1) immune responses [24,25,41,42].
Though many factors coordinate the generation of type I
immunity, IL-12 is a central figure; required for optimal
differentiation of naïve CD4
+
T cells into mature Th1
effector cells and able to induce the secretion of IFN-γ by
NK cells and CD8
+
T cells [24, 25]. Thus, based on a
significant degree of sequence and structural homology, it
was predicted that, like IL-12, IL-27 could promote Th1
responses [3]. In accord with this hypothesis, recombinant
IL-27 can augment proliferation and secretion of IFN-γ by
naïve CD4
+
T cells [3,39,40] and when combined with
IL-12, can synergize to induce IFN-γ production by human
NK cells (Fig. 2) [3]. Correspondingly, naïve WSX-1

deficient CD4
+
T cells produce less IFN-γ than wild-type
counterparts when cultured under non-polarizing
conditions (Fig. 2) [21,36,37,39,40]. Likewise, during in
vitro Th1 differentiation with IL-12 and high doses of either
αT-cell receptor antibody or ConA, WSX-1
–/–
CD4
+
T
cells produce less IFN-γ than wild-type counterparts
(Fig. 2) [36,37,39,40].
Consistent with in vitro experiments demonstrating the
ability of IL-27 to promote IFN-γ production, early studies
also showed that WSX-1
–/–
mice have enhanced
susceptibility to infection with intracellular pathogens
(Fig. 3). In resistant mouse strains, infection with
protozoan parasite Leishmania major results in the
development of CD4
+
T cell dependent Th1 responses
that mediate parasite clearance [43]. However, L. major
infected WSX-1
–/–
mice display acute defects in IFN-γ
production and lesion resolution (Fig. 3) [37,43,44].
Similarly, in WSX-1

–/–
mice, reduced Th1 responses are
evident upon challenge of an avirulent strain of
mycobacterium (bacille Calmette-Guérin [BCG]; Fig. 3)
[37]. During infection with Listeria monocytogenes,
receptor deficient animals exhibit defective bacterial
Available online />Figure 2
The paradoxical pro- and anti-inflammatory properties of IL-27. Through
ligation of its cognate receptor, IL-27 influences a range of immune cell
lineages. This figure summarizes the effects of IL-27 treatment or IL-27
receptor deficiency on mast cells, monocytes, NK cells, NK T cells,
CD4
+
T cells and CD8
+
T cells. References are listed as bracketed
citations in the far right column of the figure. IFN, interferon; IL,
interleukin; NK, natural killer; TNF, tumor necrosis factor.
228
clearance and IgG
2a
antibody class switching, both
functions that are associated with IFN-γ production (Fig. 3)
[36]. Furthermore, since many of the effector mechanisms
required for resistance to intracellular infection are also
crucial in immunity to cancer, it is not surprising that in a
model of murine carcinoma, transgenic overexpression of
IL-27 leads to increased in vivo CD8
+
T cell IFN-γ

production, cytotoxicity and tumor clearance (Fig. 2) [45].
Thus, due to the evidence that IL-27R signaling can
promote type I inflammatory responses, a consensus
emerged that, like IL-12, IL-27 is necessary for the
efficient induction of Th1 responses [25,46–50].
Although the molecular mechanisms controlling IFN-γ
production are complex, it is well established that
activated STAT transcription factors play a vital role. IL-27
can induce limited phosphorylation of STAT4, the same
signaling pathway employed by IL-12 to polarize Th1
effector cell populations [40]. Furthermore, by activating
STAT1, IL-27 promotes expression of T-bet, a
transcription factor whose target genes, particularly
IL-12Rβ2 and IFN-γ, are essential components of Th1
responses [6,39,40]. However, since other cytokines,
such as IFN-α and IFN-γ, also induce T-bet, the
requirement for IL-27/IL-27R in the development of Th1
responses is not absolute [41]. In fact, despite acute
defects in pathogen induced IFN-γ production, WSX-1
–/–
mice eventually develop the Th1 responses required for
control of L. major and BCG infections (Fig. 3) [37,44].
Thus, in spite of evidence that IL-27 can promote IFN-γ
production, a requirement for this cytokine in the
development of protective type I immunity appears
transient.
Interleukin-27 can inhibit immune effector
cell functions
Although many IL-6/IL-12 family cytokines have
proinflammatory effects, it is becoming clear that some,

particularly those that signal through GP130, can also
suppress inflammatory responses [32,51]. Thus, despite
the literature that describes a role for IL-27 in the
development of Th1 responses, there is also evidence that
WSX-1 signaling can inhibit inflammatory processes.
Several groups have reported increased proliferation of
WSX-1 deficient CD4
+
T cells during in vitro culture
(Fig. 2) [21,22,36,37]. However, since treatment with
recombinant IL-27 can also enhance the expansion of
activated CD4
+
T cells, the role of this cytokine/receptor
pairing in the regulation of proliferation remains unclear
(Fig. 2) [3].
A similar paradox exists regarding the effects of IL-27R
signaling on the production of IFN-γ by CD4
+
T cells.
When activated with a high mitogenic dose (ConA or αT-
cell receptor monoclonal antibodies), WSX-1 deficient
CD4
+
T cells produce reduced amounts of IFN-γ during in
vitro Th1 differentiation (Fig. 2) [36,37,39,40]. In contrast,
with low dose antigenic stimulation in the presence of IL-
12, WSX-1
–/–
and EBI3

–/–
CD4
+
T cells produce
significantly more IFN-γ than wild-type counterparts
(Fig. 2) [21,52]. Because a similar percentage of wild-type
and WSX-1
–/–
cells become IFN-γ positive during these
studies, the increased accumulation of IFN-γ in WSX-1
deficient Th1 cultures is likely to be a secondary
consequence to enhanced CD4
+
T cell proliferation [21].
Thus, in the presence of IL-12, IL-27 is not required for
optimal Th1 differentiation but, instead, appears to
regulate the proliferation of effector T cells.
Although production of IFN-γ is necessary for immunity to
intracellular pathogens, aberrant Th1 responses can lead
to the development of inflammatory diseases [2,24,25,41,
42]. While it may be dispensable for the generation of in
vivo Th1 responses, several studies suggest that IL-27R
signaling is crucial for the suppression of infection-
induced immunity. Following challenge with the
intracellular protozoan Toxoplasma gondii, WSX-1
–/–
mice
generate robust Th1 responses and control parasite
replication (Fig. 3) [21]. However, during the acute phase
of infection, these animals develop a lethal, CD4

+
T cell-
dependent inflammatory disease that is characterized by
immune-mediated pathology and elevated splenocyte
production of IFN-γ and IL-2 (Fig. 3) [21]. Together with
the increased T cell activation and proliferation observed
Arthritis Research & Therapy Vol 6 No 5 Villarino and Hunter
Figure 3
Analysis of infection-induced immune responses in IL-27 receptor
deficient mice. The availability of receptor deficient mice has allowed
researchers to explore the role of IL-27 in vivo. This figure summarizes
the immune response of WSX-1 -/- mice upon challenge with various
prokaryotic and eukaryotic pathogens. References are listed as
bracketed citations in the far right column of the figure. BCG, bacille
Calmette-Guérin; IFN, interferon; IL, interleukin, TNF, tumor necrosis
factor.
229
in T. gondii infected WSX-1
–/–
mice, these findings
suggest that IL-27 may have inhibitory effects on parasite
induced Th1 responses [21].
Further supporting an anti-inflammatory role for IL-27, is
the finding that WSX-1
–/–
mice develop immune-mediated
liver necrosis during infection with Trypanosoma cruzii
(Fig. 3) [53]. Since hepatic T and NK cells from infected
WSX-1
–/–

mice produce more IFN-γ and tumor necrosis
factor (TNF)-α than wild-type cohorts and in vivo
neutralization of IFN-γ can ameliorate pathology in
receptor deficient animals, it is likely that dysregulated Th1
responses mediate the liver damage (Fig. 3) [53].
Likewise, when compared with wild-type counterparts,
WSX-1
–/–
mice display enhanced sensitivity to ConA
induced hepatitis [54]. In this model of acute inflammation,
WSX-1
–/–
mice display enhanced T and NK T cell
production of IFN-γ and the severe liver pathology
observed in these animals can be curbed through
depletion of IFN-γ, CD4
+
cells or NK1.1
+
cells [54].
Together, these studies suggest that in the presence of
strongly polarizing inflammatory responses, such as those
elicited by systemic parasitic infection, the ability of IL-27
to promote Th1 responses becomes secondary to its role
in the suppression of effector cell proliferation and
cytokine production.
Given the Jak/STAT signaling cascade initiated by WSX-1
ligation, several molecular mechanisms can be proposed for
the inhibitory effects of IL-27R signaling on Th1 responses.
While the proinflammatory effects of STAT1 activation were

recognized first, it has also become apparent that this
signaling pathway can inhibit T cell responses [38]. Type I
(IFN-α/β) and type II (IFN-γ) interferons, which signal
primarily through STAT1, can inhibit T cell production of
IFN-γ and proliferation, respectively [55,56]. Also, when
compared with wild-type counterparts, T cells from T. gondii
infected STAT1 deficient mice display enhanced
proliferation, activation marker expression and IFN-γ
production [57]. However, currently, the molecular
mechanisms that mediate the inhibitory properties of STAT1
signaling remain poorly understood.
Although STAT3 phosphorylation has been well
characterized as an inhibitory event in monocytes, a role
for this pathway in the suppression of effector T cells has
also emerged. For instance, the ability of IL-6 to inhibit
CD4
+
T cell production of IFN-γ during in vitro Th1
differentiation is dependent on STAT3 activation and its
induction of SOCS (suppressors of cytokine signaling)
family proteins [58]. Furthermore, like WSX-1
–/–
animals,
mice deficient in IL-10, a powerful anti-inflammatory
cytokine that also activates STAT3, succumb to a lethal
inflammatory disease during acute toxoplasmosis [59].
However, because IL-10 acts primarily on macrophages
and DCs to limit the expression of factors that promote
Th1 responses, it is likely that IL-27 signaling represents a
novel and direct means by which infection induced T-cell

functions can be suppressed.
While the studies described above indicate that WSX-1
signaling can inhibit infection-induced Th1 responses, it
has also been reported that IL-27 negatively regulates the
generation of type II (Th2) inflammatory responses.
Appropriate differentiation of CD4
+
Th2 effector cells,
classically associated with the production of IL-4, IL-5 and
IL-13, is indispensable for resistance to helminth infection,
while dysregulated Th2 responses are pathogenic in
several diseases, including asthma and allergy [42].
Several pieces of evidence suggest that the increased
susceptibility of WSX-1
–/–
mice to intracellular pathogens
is associated with the development aberrant Th2
responses. For example, the elevated parasitemia
associated with T. cruzi infection of receptor deficient
animals can be reduced through in vivo neutralization of
IL-4 and is not associated with a corresponding defect in
IFN-γ production (Fig. 3) [53]. Accordingly, T. cruzi
infection of WSX-1
–/–
mice leads to increased production
of IL-4, IL-5 and IL-13 by CD4
+
and NK1.1
+
T cells (Fig. 3)

[53]. Moreover, WSX-1
–/–
NK T cells produce more IL-4
than wild-type cohorts during ConA induced hepatitis and
the enhanced liver pathology noted in these animals can
be curbed through systemic administration of anti-IL-4
antibody [54].
Since the morbidity associated with T. cruzi infection of
WSX-1
–/–
mice is mediated, in part, by the development of
aberrant Th2 responses, it is possible that a similar
mechanism may contribute to the delayed resolution of
Leishmania infection in these animals. During acute
leishmaniasis, neutralization of IL-4 restores the ability of
WSX-1
–/–
mice to control parasite replication and promotes
the resolution of inflammatory lesions (Fig. 3) [44]. Since
blockade of IL-4 also results in complete recovery of IFN-γ
production in WSX-1
–/–
animals, it is clear that the ability
of IL-27 to enhance Th1 differentiation is not required for
resistance to this parasite [44]. Thus, an alternative
interpretation for Leishmania susceptibility in receptor
deficient mice is that enhanced acute Th2 responses
inhibit the initial expansion of protective Th1 cells [44].
Accordingly, lymphocytes from WSX-1
–/–

mice that have
been infected for seven days produce significantly more
IL-4 than wild-type cohorts after ex vivo stimulation with
Leishmania antigen (Fig. 3) [37,44]. In fact, even after
infected WSX-1
–/–
mice have developed protective Th1
responses, IL-4 transcription is maintained and elevated
Th2 dependent antibody titres are detected [44].
While it appears that IL-27R signaling is required to
suppress the development of pathogenic Th2 responses
in several disease models [21, 53, 54], studies assessing
the role of WSX-1 during infection with the intestinal
Available online />230
dwelling helminth Trichuris muris suggest that it may also
regulate the development of protective type II immunity
(Fig. 3) [22]. Genetically resistant wild-type animals do not
generate the Th2 responses required for worm expulsion
until approximately 3 weeks post infection but, by day 14,
all WSX-1
–/–
animals have eradicated larval worms (Fig. 3)
[22]. At this early time point, receptor deficient mice
display increased Th2 dependent intestinal goblet cell
hyperplasia, mastocytosis and enhanced production of IL-
4, IL-5 and IL-13 during ex vivo lymphocyte recall assays
[22]. Since wild-type animals do not acquire this hyper-
resistant phenotype when Th1 responses are effectively
blocked in vivo, it is unlikely that the accelerated
development of Th2-type immunity in WSX-1

–/–
mice is
the secondary consequence of an intrinsic defect in IFN-γ
production [22]. Instead, IL-27 appears to have direct
inhibitory effects on the generation of mucosal Th2
responses that are independent of its ability to enhance
IFN-γ production.
While appropriate induction of mucosal Th2 responses is
required for resistance to T. muris, production of type I
cytokines results in chronic infection [60,61]. In resistant
mouse strains, inoculation with a high dose of parasites
leads to the generation of protective type II immunity but
low dose infection results in the development of Th1
responses and persistent infection [61]. However, a low
dose T. muris infection does not result in the
predominance of Th1 responses in WSX-1
–/–
mice and,
instead, these animals develop protective Th2 responses
that mediate parasite clearance (Fig. 3) [23]. Although
neutralization of IL-12 and IFN-γ can lead to worm
expulsion in low-dose infected wild-type mice [60],
defective IL-27 dependent Th1 responses are not solely
responsible for the enhanced helminth resistance of WSX-
1 deficient animals. In fact, since in vivo administration of
IL-12 restores parasite-specific IFN-γ responses but does
not lead to chronic infection [23], it is likely that, as in the
case of high dose infection, elevated mucosal Th2
responses mediate enhanced resistance in low dose
infected WSX-1

–/–
animals. In sum, these data suggest
that IL-27 signaling can directly regulate the kinetics and
intensity of protective type II immunity through the
suppression of helminth induced Th2 responses.
While these in vivo studies support the hypothesis that
IL-27 can directly down-regulate Th2 processes, several
in vitro experiments provide possible cellular and
molecular mechanisms for this effect. In CD4
+
T cells,
recombinant IL-27 can inhibit expression of GATA-3 [40],
a transcription factor that mediates the acquisition of
several important Th2 attributes in differentiating CD4
+
T
cells [42]. When treated with IL-27, reduced GATA-3
transcription is reflected in decreased IL-4 production by
naïve CD4
+
T cells that have been cultured under Th2
polarizing condition [22,40]. Concurrent with these
findings, WSX-1
–/–
CD4
+
T cells produce more IL-5 and
IL-13 than wild-type counterparts during in vitro Th2
differentiation [22]. Because at least one complete cell
cycle is required for CD4

+
T cells to become Th2 effectors
[62], it is likely that the elevated proliferation noted in WSX-
1
–/–
CD4
+
T cells, in combination with a lack of IL-27
dependent GATA-3 inhibition, allow for a more rapid
outgrowth of mature Th2 cells from a pool of naïve
precursors. Therefore, by limiting the proliferative capacity
of naïve CD4
+
T cells and inhibiting the expression of a key
Th2 transcription factor, IL-27 appears to regulate the
potency of nascent type II inflammatory responses.
While the studies discussed here clearly demonstrate that
IL-27 has profound effects on T cells and NK cells,
expression of IL-27R on other immune cell lineages
suggests that it may also regulate myeloid cell functions
(Fig. 2) [34]. During T. cruzi infection, hepatic WSX-1
deficient macrophages produce more IL-6 and TNF-α than
wild-type counterparts (Figs 2 and 3) [53]. Since ablation
of STAT3 in myeloid cells results in elevated production of
IL-6, TNF-α and IL-12 [63], it is possible that a lack of
IL-27 induced STAT3 phosphorylation contributes to the
enhanced secretion of inflammatory cytokines observed in
T. cruzi challenged WSX-1
–/–
animals. Similarly, in

WSX-1
–/–
mice, deficient STAT3 activation may factor in
the enhanced IL-12 production and increased mast cell
activation that is observed during T. gondii and T. muris
infection, respectively (Figs 2 and 3) [21, 22]. Although in
vivo studies suggest that IL-27R signaling can suppress
monocyte and mast cell functions, in vitro experiments
propose that it can also have proinflammatory effects in
these cells (Fig. 2). IL-27 can directly induce expression of
IL-1 and TNF-α by primary mast cells and production of
IL-1, TNF-α, IL-12p35 and IL-18 by monocytes [34].
Therefore, while many questions remain about the
functional consequences of IL-27 signaling in myeloid
cells, it is becoming clear that this cytokine is critical in the
regulation of both innate and adaptive elements of
parasite induced immunity.
Conclusion
Initial studies indicated that IL-27, like IL-12, can promote
T and NK cell IFN-γ production while, similar to IL-12R
deficiency in humans and mice, WSX-1
–/–
T cells are
defective in the generation of Th1 responses (Fig. 2).
However, subsequent work has reported that the IL-27/
IL-27R interaction is not strictly required for the generation
type I immunity. Thus, while WSX-1
–/–
mice exhibit acute
defects in the production of IFN-γ during infection with L.

major, these animals also develop exaggerated Th1
responses upon infection with T. gondii and T. cruzi
(Fig. 3). One key difference between these infections is
the prevalence of innate immune cell activation and the
abundance of IL-12, a key factor for the optimal
development of Th1 responses [43]. The acute response
Arthritis Research & Therapy Vol 6 No 5 Villarino and Hunter
231
to L. major is localized to the site of infection and is not
associated with NK cell activation or systemic IL-12
production [43]. In contrast, T. gondii and T. cruzi are
disseminating infections that induce strong innate immune
responses and high serum levels of inflammatory
cytokines [43]. In these infectious diseases, innate
involvement promotes the secretion of IL-12 by
macrophages and DCs and thereby creates a highly
polarizing, Th1 environment for T cell priming [43]. Under
such conditions, the ability of IL-27 to enhance IFN-γ
production may be secondary to its effects on clonal
expansion and contraction. In support of this hypothesis,
infection of WSX-1
–/–
mice with T. gondii leads to acute
mortality mediated by a pathogenic accumulation of
activated Th1 cells (Fig. 3) [21]. Furthermore, the
accelerated helminth resistance observed in WSX-1
–/–
mice indicates that IL-27 may also suppress infection
induced Th2 responses (Fig. 3) [22, 23]. Thus, it can be
hypothesized that while IL-27 may not dictate the polarity

(i.e. Th1 vs. Th2) of a nascent response, it may be
essential in regulating the kinetics and intensity of
infection induced immunity.
Many of the cytokines produced to combat pathogenic
challenge are also characteristic of chronic inflammatory
disorders. Accordingly, production of IL-6/IL-12 family
cytokines is associated with the development of
rheumatoid arthritis [4,51,64]. In murine models, IL-6 can
promote the onset and severity of joint inflammation
[51,64] but deficiencies in this cytokine can also
exacerbate arthritic pathology [65]. Early studies identified
the ability of IL-12 to aggravate disease [66,67] but recent
work has determined that IL-23, and not IL-12, is required
for the development of arthritis [68]. Thus, similar to the
paradoxic functions of IL-27 during parasitic infection, it is
apparent that IL-6/IL-12 family cytokines can have both
pro- and anti-inflammatory effects on the development of
autoimmune pathology.
While the detection of IL-27 in granulomatous tissues
from individuals with sarcoidosis and Crohn’s disease
suggest that it may factor in the regulation of immune
mediated pathologies [7], the pleotropic nature of this
cytokine makes its role in arthritis difficult to predict. By
enhancing Th1 responses directed towards self-antigens,
it is possible that IL-27 may promote disease. In
agreement with this hypothesis, a recent study indicated
that in vivo neutralization of IL-27 reduces the severity of
adjuvant-induced arthritis in rats and, in this model,
amelioration of disease is associated with a reduction in T-
cell proliferation and inflammatory cytokine production

[69]. However, it is also possible that IL-27 can have
inhibitory effects on the inflammatory responses
associated with arthritis. By increasing the amount of
GP130 available for inclusion in the IL-6 receptor,
WSX-1
–/–
animals may display increased rheumatoid
pathology. Furthermore, since STAT1 deficiency is
associated with increased chronic pathology in zymosan
induced arthritis [70], it is possible that signaling through
the IL-27R may provide a direct inhibitory signal to curb
disease progression. Similarly, reports of spontaneous
colitis and arthritis in mice lacking the STAT binding sites
of GP130 support a role for IL-27 in protection from
autoimmune disease [71]. Since IL-6 is closely associated
with the development of arthritis and mice deficient in this
cytokine do not develop inflammatory disease unless
prompted by exogenous mitogens [51,64], it is likely that
the heterodimeric IL-27R mediates some of the inhibitory
effects associated with GP130 dependent STAT
activation. When considered in the context of the aberrant
adaptive immune responses noted in pathogen challenged
WSX-1
–/–
mice (Fig. 3), these studies suggest that IL-27
may be a general suppressor of cell mediated
inflammatory responses. Thus, given the viability of
WSX-1 deficient animals, IL-27 and the IL-27R may
represent safe and effective targets for future inflammatory
therapeutics.

Competing interests
Amgen, DNAX and Genentech have provided reagents
and support for studies on IL-27 and WSX-1.
Acknowledgement
Grant support was provide by the State of Pennsylvania and NIH grant
41158 with a Minority Supplement to AV (A10662).
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